Imlach Wendy L, Finch Sarah C, Dunlop James, Dalziel Julie E
AgResearch, Grasslands Research Centre, Palmerston North 4442, New Zealand.
Eur J Pharmacol. 2009 Mar 1;605(1-3):36-45. doi: 10.1016/j.ejphar.2008.12.031. Epub 2009 Jan 10.
Lolitrem B is an indole-diterpenoid neurotoxin which is the main causative agent of ryegrass staggers, an animal disease associated with tremors and incoordination. It is also a potent inhibitor of large conductance calcium-activated potassium (BK) channel activity (IC(50)=4 nM). Furthermore, we have recently shown that the motor function deficits induced by lolitrem B are specifically mediated by BK channels, making the toxin a valuable tool for investigating the molecular function and physiological roles of these channels. To determine what structural features of BK channel agents are required for high potency, the effect of lolitrem B and seven structurally-related lolitrems on BK channel activity has been measured. Concentration-responses and conductance-voltage (G-V) relationships were determined for each compound and related to the different structure types. This study has identified seven new BK channel inhibitors and has allowed the identification of two key structural features required for high potency BK channel activity by lolitrems.
洛替米星B是一种吲哚二萜类神经毒素，是黑麦草蹒跚病的主要致病因子，这是一种与震颤和共济失调相关的动物疾病。它也是大电导钙激活钾（BK）通道活性的有效抑制剂（IC(50)=4 nM）。此外，我们最近发现，洛替米星B诱导的运动功能缺陷是由BK通道特异性介导的，这使得该毒素成为研究这些通道分子功能和生理作用的宝贵工具。为了确定BK通道药物高效力所需的结构特征，我们测量了洛替米星B和七种结构相关的洛替米星对BK通道活性的影响。测定了每种化合物的浓度-反应和电导-电压（G-V）关系，并将其与不同的结构类型相关联。本研究鉴定出七种新的BK通道抑制剂，并确定了洛替米星高效BK通道活性所需的两个关键结构特征。
